Some remarks on the recent FDA approval of the anti-obesity med lorcaserin that we’ve been blogging about for 5 years

On June 27, for the first time in 10+ years, the FDA approved an anti-obesity med. This is big news. It means that the Federal Gov’t is getting its act together about actually treating obesity as a medical condition, despite vested interests in keeping the nation fat.

But more than that, this may also mean that the FDA isn’t totally in the pocket of Wall Street. And, last but not least, it may mean that there is a pill to help people not eat so much so they will slim down and be healthier.

The drug that was approved was the one we’ve been blogging about almost since this blog started in 2007, the one with the generic name “lorcasein.” The label indication is for weight loss and includes people who are obese (BMI ≥30) or those overweight (BMI ≥27) with an obesity comorbidity, like high blood pressure. The drug reduces appetite and is taken as a blue pill, twice a day. The FDA recommends that patients who have not lost 5% of body weight by week 12 stop taking the drug, and additional juvenile and cardio vascular studies will be conducted post-approval.

As we’ve blogged before, lorcaserin is thought by some to be a safe version of the fenfluoramine, the “fen” of fen-phen(termine) fame that worked so well. (See our post: “Lorcaserin: The “Chevy” of weight loss meds” — this post had 87 comments, and we should have realized that this portended the later commotion with the stock and the percerption of improprieties in the FDA review process.) In its heyday, fen-phen had something like 18MM scripts written for 2.5MM patients. One can see how this would be a terrific market for a drug company if the presumed fenfluramine glitches could be fixed. (We’ve always thought that the heart-valve issue was trumped up anyway, as fenfluramine was banned just at the launch of Lipitor, a Pfcoincidence?) But, there is no word of any Belviq combos, particularly with phentermine. If this works about as well as fen-phen, without the heart problems and without any other issues, then we think this drug could be the thing that bends the cost curve of health care by reducing obesity in a significant portion of the population (given the fen-phen data).

OK, youngins’, way back in the autumn of 2007, when we first started blogging about this, we didn’t think much of lorcaserin, except that safe fen-phen seemed like a good idea to us, and good for the biopharma management for finding an NCE (new chemical entity) to put into the clinic (Then it was called “APD-356″). We assumed lorcaserin was a first-in-class (a “Chevy” to use a dated analogy), but not necessarily a best-in-class. This isn’t to preclude a best-in-class version; if we ran the program, we’d have a sustained release version that lasted longer, and moreover, a new improved version that had higher specificity for the business end of the 5-HT2c-1A receptor, the receptor for which the drug is an agonist.

Something that we noted but didn’t fully appreciate was the diabetes angle — there may be a glycemic-control aspect to the 5-HT2c receptor. And so, lorcaserin, being an agonist toward the 5-HT2c1A receptor, may be useful in treating diabetes. Lorcaserin clinical trials on people with diabetes showed an improvement in markers, and so perhaps this may be an indication sometime later.

Also before the FDA are other molecules with other modes of action, like leptin and the poly-psych-med approach. We are unimpressed.

Although we think leptin and its various forms are interesting — and it may be the biological molecule that has had the most money thrown at it with the fewest actual results — our view is that having an injectable for a weight loss med is a tough sell. Would you want to be the detailer going into the doctor’s office after the lorcaserin rep? A hypothetical conversation: Doctor: “My patients can get weight loss by swallowing a teensy pill and a cup of water.” Leptin rep: “They can also get weight loss by injecting a horse needle full of leptin.” Perhaps intra-nasal leptin will be the key, although if leptin is anything like insulin, dosing will need to be very precise. (That’s also why we don’t like inhalable insulins — it seems that what you get with dosing convenience, you lose with dosing accuracy, but that’s just our view.) We’re also skeptical of the amylins, but that’s only because we recall hearing (unsubstantiated) rumors that all that weight loss was due to nausea. That’s only a rumor floating around way back when Amylin was rumored to be up for sale for the first of many times that we heard about. (Amylin was just acquired this past week or so — coincidence that it was the week the FDA greenlights an obesity med? Does removal of the FDA bar against anti-obesity meds have any connection to 2012 bonuses? We digress.) Be that as it may, we’d be interested to see if amylin + leptin = weight loss due to throwing up.

. . . I never understood this line of drug development — why would you want to take a single compound and combine it with another one?

The easiest drug development, in general, is to go after a single-activity which is pro-active — it causes something to happen (as opposed to inhibiting something from happening). The reason is that nature always has compensatory mechanisms, so if you inhibit something, your body usually finds a way around it.

Once you have a drug that is pro-active, try to make it very specific. “More” is not better. This is a matter of control. You want a specific, measurable result – not something that will produce scattershot results.

If you’re dealing with an inhibitor, best to keep it simple so you can titrate the inhibition — it doesn’t have to be binary (on/off), and you don’t have to have complete inhibition. But, like some of the antibody-based drugs, 80/20 rule may be enough.

The trouble is that once you put the three agonists in a single pill, you lose the ability to titrate for a single receptor. It’s a one-size-fits-all. This immediately complicates your clinical trials because now you have too many variables — people who have a reaction to agonist A, B, or C or maybe the AB combination or maybe the BC or whatever. It will be interesting to see how they can parse the data on that one.

I don’t know, but adding dopamine to the mix seems unnecessary for weight loss where all you need to do is to go to the appetite region, 5HT2c. . .

Two other anti-obesity meds in the clinic combine psych meds with phentermine, the “phen” of fen-phen. The trouble in our view is that (a) the psych meds have all sorts of effects apart from anti-appetite, and (b) phentermine is chemically similar to speed and is currently prescribed for only about 3 months at a shot. It’s just easier to separately titrate phentermine.

As far as marketing, the sales will be handled by Eisai, a big pharma out of Japan. The reps may be in something of a bind: our guess is that lorcaserin works with phentermine the same as fen-phen, which is phenomenally well for some people. But, the reps can’t promote off label. So what to do? Accidentally drop a stack of reprints of a lorcaserin/phentermine study on the medical center office doorstep? What will the reps say when asked about phentermine? “We can’t promote for that,” wink wink nudge nudge. We’ve always said that this should be set up with Jenny Craig or Weight Watchers or some other retail outlet by having storefront clinic.

The tradename will be “BELVIQ®” at least in the US. * The name “BELVIQ” is different from what had been reported by various presumably unofficial sources, “LORQESS.” This last minute switcheroo is a terrific strategy if you’ve screwed up by not checking that Lorphen (i.e., Lorqess + phentermine) isn’t the name of something else (like, Lorphen eyedrops). Good save Arena marketing consultants! Anyway, “BELVIQ” reminds us of the name “Belva,” a name that was relatively popular from 1890 until 1960 when the popularity fell off a cliff. “Belva” means “beautiful view.” But what will the extended release version be called (assuming there is one)? Belviq-XT?

The whole saga of lorcaserin FDA regulatory review and the related company stock is like a bad Icelandic opera that ends with a volcano instead of a fat lady singing. OK that’s a tortured analogy that doesn’t make any sense but it feels that way and feelings are more important than facts, no? Oh wait, now I sound like a financial journalist. Act I opens with the FDA advisory committee meeting in September 2010, after testing something like 8000+ patients, including continual echocardiograms to make sure there are no heart problems (there weren’t, despite some fear mongering otherwise). The outcome of the meeting? These “experts” would not recommend approval because of concerns about tumors on rats — the kind of rats that get tumors just sitting there, because they are lab rats designed to get tumors. (Our posts here, here, here, here, and here. And here.) And then, there was a “readjudication” of rat tumor data, in our view, sort of a show trial for the FDA to save face by having experts look at rat tumors. While we’ve read that there was some miscommunication between the FDA and the drug sponsor, the whole thing came out of the blue, particularly since the FDA advisory committee meeting didn’t have a rat cancer expert present so all the other experts just assumed “oooo rat tumors, better not recommend approval because we don’t know what this means.” Finally, after blinded readjudication by independent experts showed no difference in rat tumors between placebo and test rats, the FDA was satisfied (unlike Wall Street analysts).

We’ve said the analysts were wrong, wrong, wrong for years now. And, we wuz right. This leads us to conclude that either analysts are totally incompetent, or, they are working schmoos who are the mouthpieces of the market making/underwriting/book running/investment banking branches. Financial journalists are also beholden. Call us Captain Obvious. Well, no one can accuse us of manipulating the market given that despite our favorable blog posts, the stock sunk like a rock.

And, so, the institutional investors and hedge funds put their money on the wrong horses so far — the horses recommended by the analysts. The Arena shorts apparently ran out of shares to cover. And we got our notice from Charles Schwab asking to lend out our Arena shares. That notice went into our paper shredder (we have a bad habit of saying “paper shredder” with a Southern Accent, like “paypa shredda” because someone with a Southern Accent once threatened to put us in such machine).

All of this is against the backdrop of investor activism. Would lorcaserin have been approved without the investor/whistleblower collectivism? Or was lorcaserin approved on its merits? Did lorcaserin get approved because the lipitor patent expired and it was politically feasible? Did the hedge funds wring all their money out of Orexigen and Vivus so they don’t care about appearances any more? We hope an insider writes a kiss-and-tell because this was the most blatant display of inside baseball we’ve ever seen in getting drug approval, and we’ve seen some doozies.